Autoimmunity and emphysema and risk of osteoporosis in smokers

吸烟者的自身免疫和肺气肿以及骨质疏松症的风险

• 批准号: 9916794
• 负责人: JESSICA BON
• 金额: $ 38.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9916794
• 关键词: Age; Alveolar Macrophages; Antibodies; Autoantibodies; Autoimmune Process; Autoimmune Responses; Autoimmunity; Binding; Binding Proteins; Biological Assay; Biological Markers; Bone Density; Cachexia; Cause of Death; Cells; Chronic Obstructive Airway Disease; Data; Dentin; Diagnostic radiologic examination; Disease; Disease Progression; Endoplasmic Reticulum; Enzyme-Linked Immunosorbent Assay; Female; Foundations; Fracture; Future; Goals; Heat shock proteins; High Prevalence; Human; Immune Targeting; Immune response; Immunoglobulin G; Immunohistochemistry; Immunologic Markers; Immunologics; Immunomodulators; In Vitro; Incidence; Inflammation Mediators; Inflammatory; Investigational Therapies; Link; Literature; Longitudinal cohort; Lung diseases; Measurement; Measures; Mediating; Molecular; Molecular Chaperones; Morbidity - disease rate; NF-kappa B; Natural History; Osteoclasts; Osteoporosis; Osteoporosis prevention; Participant; Pathogenesis; Pathogenicity; Pathologic; Patient Selection; Patients; Physical activity; Physiological; Population; Prevalence; Prevention strategy; Process; Production; Proteins; Pulmonary Emphysema; Reaction Time; Reverse Transcriptase Polymerase Chain Reaction; Risk; Risk Factors; Risk stratification; Roentgen Rays; Role; Scanning; Series; Smoker; Smoking Status; Stains; Steroids; Testing; United States; Variant; Woman; X-Ray Computed Tomography; airway obstruction; biological adaptation to stress; bone; bone resorbing activity; bone turnover; clinically significant; cohort; cytokine; endoplasmic reticulum stress; falls; follow-up; glucose-regulated proteins; improved; insight; male; men; mortality; novel; nuclear factors of activated T-cells; osteoporosis with pathological fracture; patient population; physical inactivity; precursor cell; public health relevance; pulmonary function; response; screening guidelines; smoking-related lung disease; targeted agent; tartrate-resistant acid phosphatase; time interval; tool; treatment strategy

 DESCRIPTION (provided by applicant): Low bone mineral density (BMD) has been linked to chronic obstructive pulmonary disease (COPD) independent of traditional osteoporosis risk factors including steroid use, cachexia, and decreased physical activity. Although the increased prevalence of osteoporosis contributes to morbidity and mortality in COPD patients, little is known regarding indications for BMD assessment or osteoporosis mechanisms in this susceptible population. The rate of BMD loss is an independent risk factor for fracture. Yet, cross-sectional dual x-ray absorptiometry (DXA) assessment of BMD provides no information about rate of BMD decline. Immunologic alterations contribute to the pathogenesis of both COPD and osteoporosis but the role of autoimmunity in COPD-related osteoporosis has not been studied. An independent association between emphysema and low BMD has been supported by the literature, but the mechanism for this association is also unknown. This project's overall goal is to study how specific autoimmune processes relate to concurrent emphysema progression and accelerated BMD decline in male and female smokers with lung disease. This goal will be accomplished through extension to six years of an already established longitudinal cohort with pre- existing baseline and two-year assessments of BMD, radiographic emphysema, pulmonary function, and autoimmune biomarker levels. The association of an autoimmune biomarker, anti-glucose regulated protein 78 (GRP78) IgG, with emphysema progression, measured by quantitative CT scan, and BMD loss, measured by serial DXA, over the six-year time interval will be studied in smokers with emphysema or airflow obstruction. A series of in vitro osteoclast studies will be performed to assess the effect of autoantibodies to GRP78, an endoplasmic reticulum (ER) chaperone protein intimately involved in the ER stress response, on osteoclast formation, proliferation, and activity. The findings from this project will identify criteria for smokers at risk of accelerated BMD loss in whom early and serial measurements of BMD may be warranted, provide insight into pathogenic mechanisms linking emphysema and osteoporosis, and provide novel targets for osteoporosis prevention and treatment strategies in patients with COPD.

 描述（由申请人提供）：低骨矿物质密度（BMD）与慢性阻塞性肺病（COPD）有关，与传统的骨质疏松症危险因素（包括类固醇使用、恶病质和体力活动减少）无关。尽管骨质疏松症患病率的增加导致 COPD 患者的发病率和死亡率，但对于这一易感人群的 BMD 评估或骨质疏松机制的适应症知之甚少。 BMD损失率是骨折的独立危险因素。然而，BMD 的横截面双 X 射线吸收测定法 (DXA) 评估没有提供有关 BMD 下降速度的信息。免疫学改变有助于 COPD 和骨质疏松症的发病机制，但自身免疫在 COPD 相关骨质疏松症中的作用尚未研究。文献支持肺气肿与低骨密度之间的独立关联，但这种关联的机制尚不清楚。该项目的总体目标是研究患有肺部疾病的男性和女性吸烟者的特定自身免疫过程如何与并发肺气肿进展和加速 BMD 下降相关。这一目标将通过将已经建立的纵向队列延长至六年来实现，其中包括现有基线和对 BMD、放射线肺气肿、肺功能和自身免疫生物标志物水平的两年评估。将在患有肺气肿或气流阻塞的吸烟者中研究六年时间间隔内自身免疫生物标志物抗葡萄糖调节蛋白 78 (GRP78) IgG 与通过定量 CT 扫描测量的肺气肿进展和通过系列 DXA 测量的 BMD 损失之间的关系。将进行一系列体外破骨细胞研究，以评估 GRP78 自身抗体对破骨细胞形成、增殖和活性的影响，GRP78 是一种与 ER 应激反应密切相关的内质网 (ER) 伴侣蛋白。该项目的研究结果将 确定有 BMD 加速损失风险的吸烟者的标准，这些吸烟者可能需要进行早期和连续的 BMD 测量，深入了解肺气肿和骨质疏松症之间的致病机制，并为 COPD 患者的骨质疏松症预防和治疗策略提供新的目标。